The discovery of the antitumor activity of 1,4-bis[(aminoalkyl)amino] anthracene-9,10-diones such as ametantrone and mitoxantrone (Zee-Cheng, R. K. V. et al., J. Med. Chem, 21, 291-294, (1978); Zee-Cheng, R. K. V. et al., J. Pharm. Sci., 71, 708-709, (1982); Murdock, K. C. et al., J. Med. Chem., 22, 1024-1030 (1979)) has led to numerous physicochemical and pharmacological studies on the tumoricidal mechanisms of these chemotypes. Krapcho, A. P. et al., J. Med. Chem., 34, 2373-2380, (1991); Morier-Teissier, E. et al., J. Med. Chem., 36, 2084-2090, (1993). A number of studies have indicated that an intercalative interaction with DNA may be a major cellular event. Denny, W. A. Anti-Cancer Drug Design, 4, 241-263 (1989). Mitoxantrone, an anthracene-9,10-dione, has gained an important position in the clinical management of leukemia and lymphomas as well as in combination therapy of advanced breast and ovarian cancers. Faulds, D. et al., Drugs, 41, 400-449 (1991). Although mitoxantrone is endowed with an improved tolerance prolife when compared with doxorubicin and other anthracyclines, significant toxic side effects, notably those associated with myelosuppression and cardiotoxicity, remain. Benekli, M. et al., Ann. Intern. Med., 126, 409 (1997).
Bailly etal. (P. Bailly, J. D. et al., Leukemia, 11, 1523-1532 (1997)) have reported that mitoxantrone shows a cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein. Several studies suggest that intercalation into DNA is a major cellular event and this intercalative interaction may serve as an anchor for the drug at specific base pair sites, which is then followed by the critical cell-killing events. The biochemical basis for the cardiotoxicity exhibited by mitoxantrone is not fully understood. It is generally believed that the in vivo reduction of the quinone moiety is probably more related to the cardiotoxic side effects of mitoxantrone than to its mechanism of cytotoxicity. Krapcho, A. P., et al., J. Med. Chem., 41, 5429-5444 (1998). The planar tricyclic system is known to intercalate into DNA base pairs and interfere in the transcription and replication processes of the cell. Johnson, R. K. et al., Cancer Treat. Rep., 63, 425-439, (1979); Lown, J. W. et al., Biochemisty, 24, 4028-4035, (1985). The DNA binding affinity (quantified as a binding affinity constant) and the dissociation rate constant for the DNA-ligand complex have been evaluated. Drug-DNA binding constants for ametantrone, mitoxantrone and related congeners with calf thymus DNA show a large sensitivity to the position and number of the OH substitutions and the nature of the charged side chain. Denny, W. A. Anti-Cancer Drug Design, 4, 241-263 (1989).
The compounds based on anthraquinone skeleton occupy a prominent position in cancer chemotherapy, with the naturally occurring aminoglycoside anthracycline doxorubicin and the aminoanthraquinone mitoxantrone both being in clinical use. These and other experimental anthraquinone derivatives are believed to act at the duplex DNA level, probably through the stabilization of a ternary complex with DNA topoisomerase II. Zunino, F. et al., Anti-Cancer Drug Des., 5, 307-317 (1990).
9-Acyloxy-1,8-dichloro-anthracene has been reported to useful in the treatment of allergic, inflammatory and tumour conditions by Hsu-Shan Huang, U.S. Pat. No. 6,372,785 (2002). In addition, the inhibition of lipid peroxidation was detected as was their ability to inhibit the telomere-addition function of the human telomerase enzyme together with their inhibition of the Taq polymerise enzyme Huang Hsu-Shan etal Chem. and Pharmaceutical Bulletin, 49(5), 969-973 (2001).
Additional references disclose 1,4- and 2,6-disubstituted or regioisomeric amidoanthracene-9,10-dione derivatives as inhibitors of human telomerase include Philip J. Perry et al. J. Med. Chem. 41, 3253-3260 (1998) and Philip J. Perry et al. J. Med. Chem. 41, 4873-4884 (1998). Zagotto, G etal. Farmaco, 55(1), 1-5 (2000) have synthesised a new class of D- and L-aminoacyl-9,10-anthraquinone derivatives as potential cytotoxic agents and correlated their activity with the configuration of the chiral aminoacyl moiety.
It is evident from the literature that free radicals and active oxygen species play a key role in both the therapeutic activity and side effects of anthracenone derivatives. The generation of free radicals from quinones occurs by addition of an electron to the quinone to form semi-quinone free radicals which then transfer an electron to molecular oxygen to afford superoxide radical anion. The resulting radical anions ultimately lead to hydroxyl radicals, which can damage cardiac tissue. Despite the attempts to rationalize the cardiotoxicity of anthracene-9,10-dione antitumor agents, few compounds have been shown to possess both good antitumor activity and little or no cardiotoxicity. Consequently there appears to be no way to predict which compounds will be cardiotoxic and which compounds will not. One is thus confronted with the major problem of designing molecules with high efficacy and no toxicity. Krapcho, A. P. et al., J. Med. Chem., 41, 5429-5444 (1998).
The present invention differs from the prior art in the sense that the compounds claimed here are partially reduced anthracenes. Therefore, they have non planar structures and differ from anthracenes, anthraquinones and anthrones, which are planar. This non planarity has therefore different implications for their mechanisms of action and typically, intercalation as it pertains to anthracene based molecules, need not apply.